An important focus of my work is development of chimeric antigen receptor T cell therapies for multiple myeloma, which is a usually incurable malignancy of plasma cells. My group was the first to design and construct CARs that specifically recognize B-cell maturation antigen (BCMA). BCMA has a very restricted expression pattern in normal tissues, but BCMA is expressed on the malignant plasma cells of multiple myeloma. The BCMA specific CARs that we have constructed specifically recognize multiple myeloma cell lines and primary myeloma cells in vitro and eradicate myeloma tumors in mice. An extensive analysis of BCMA expression in normal human tissues by immunohistochemistry and quantitative PCR has been conducted. Except for expression by normal plasma cells, BCMA expression was not detected in nomal human organs by immunohistochemistry. The first clinical trial of anti-BCMA-CAR-transduced T cells for treating advanced multiple myeloma was opened for enrollment in September, 2014. James Kochenderfer was Principle Investigator of this trial. Twenty -six patients were treated on this trial. There have been impressive responses on this trial, which were the first demonstrated examples of elimination of measurable multiple myeloma by CAR T cells. This work led to a publication in the journal Blood in 2016. In conjunction with Bluebird Bio, Inc. We have developed a new anti-BCMA CAR that Bluebird licensed from the NCI. This new CAR was developed in my laboratory and modified by bluebird bio. This new CAR is being tested in a world-wide phase I and II multicenter trials conducted by Celgene, Inc. I am a site PI of the phase I trial of this CAR. The longest ongoing complete remission from this trial is 3 years in duration. Results from his trial were published in the New England Journal of Medicine in May 2019; James Kochenderfer was senior author of this paper. Another general area of research on CAR T-cell therapies for multiple myeloma is improving the design of CARs. We have a project looking at how changes in the structure of the hinge region of CARs can be quite important in determining in vivo efficacy of CARs. We have shown that very small changes in the hinge region of anti-BCMA CAR T cells can affect the in vivo function of CAR T cells. We have designed novel CARs with fully-human heavy-chain-only antigen-recognition domains, and a clinical trial testing one of these CARs, designated FHVH33-CD8BBZ, is underway. We hypothesize that fully-human heavy-chain-only anti-BCMA CAR T cells will be less immunogenic than traditional CARs with single-chain variable fragment antigen-recognition domains. 12 patients have been treated on this clinical trial, and 10 of the 12 patients have had objective responses. We are also designing CARs against antigens other than BCMA because multiple myeloma is a phenotypically heterogeneous malignancy in many cases, so targeting more than one antigen might be necessary to effectively induce long progression-free intervals of multiple myeloma. We have designed CAR constructs containing a CAR targeting signaling lymphocyte activation molecule family member 7 (SLAMF7). We have completed preclinical development of a construct that encodes an anti-SLAMF7 CAR and a suicide gene. The suicide gene allows on-demand elimination of the CAR-expressing T cells. The suicide gene is activated by a dimerizer agent called Rimiducid. After dimerization, caspase 9 is activated, which leads to apoptosis of the CAR-expressing T cells. The anti-SLAMF7 p;lus suicide gene construct is designated IC9-Luc90-CD828Z. We have initiated a clinical trial of IC9-Luc90-CD828Z T cells..